KR20050086515A - Process for converting a cis-trans mixture of substituted benzylidene amines into the pure cis isomer - Google Patents

Abstract

A process for interconverting a mixture of cis-trans erythro-threo isomers of a compound of formula I into the substantially pure cis isomer. Cis isomers of formula I are usefull intermediates in the synthesis of cis isomers of benzamide piperidine compounds which exhibit activity as NK-1 receptor antagonists.

Description

PROCESS FOR CONVERTING A CIS-TRANS MIXTURE OF SUBSTITUTED BENZYLIDENE AMINES INTO THE PURE CIS ISOMER}

The present invention relates to a process for the preparation of the pure cis isomer from a mixture of cis-trans isomers of substituted benzylidene amines.

Substituted benzylidene amines of the present invention, more specifically the compounds defined by formula (I) below, are useful intermediates in the preparation of benzamide piperidine compounds that are active as NK-1 receptor antagonists. Synthesis of this cis isomer provides a novel stereospecific pathway to cis benzamide piperidine which is biologically more active in high yield.

The stereo-selective route to cis-rich benzamide piperidine is US Patent Application Serial No. 09 / 811,218, filed March 16, 2001, which is incorporated by reference in its entirety. 01/77100. Resolution of the isomer-rich mixture into the desired pure isomer requires an additional step accompanied by the loss of effective product. The present invention provides an alternative and more direct method for establishing cis stereochemistry.

Summary of the Invention

The present invention provides a method for preparing the pure cis isomer from a mixture of cis-trans isomers of the compound of formula (I) comprising the following steps:

a. Dispersing a mixture of cis and trans isomers of formula (I) in an inert solvent wherein the cis isomer of formula (I) is substantially less soluble than the trans isomer;

b. Heating the dispersion such that the trans isomer is completely dissolved and the cis isomer is dissolved at least 10% by weight;

c. Maintaining a heating step such that the cis and trans isomers are interconverted;

d. Cooling the mixture to crystallize into cis isomers; And

e. Separating the crystalline cis isomer from the solvent;

Where

R is C _1-5 alkyl and Ar is phenyl or naphthyl optionally mono- or di-substituted by C _1-5 alkyl, C _1-5 alkoxy, halogen, trifluoromethyl, ester or amido .

The method comprises a series of steps in which the cis isomer starts with a dispersion of the isomeric mixture in a selected solvent having a lower solubility than the trans isomer. The isomers are then interconvertible by heating the starting dispersion and maintaining adequate temperature and sufficient time to form a solution equilibrium.

At least about 10% by weight of the cis isomer is dissolved and the dispersion is heated to balance the cis and trans isomers and maintained for an extended period of time. In a preferred embodiment, the trans isomer is completely dissolved and at least a portion of the cis isomer is dissolved during the heating step. In a preferred embodiment, the equilibrium ratio of cis to trans isomers in solution during the heating step is 3: 1.

Upon cooling of the solution, less soluble cis isomers separate into pure crystalline form.

In step (a) the starting mixture of cis and trans isomers is provided in a weight ratio of cis to trans about 60:40 to about 40:60. In a preferred embodiment the ratio is 50:50.

Suitable solvents are those in which the trans isomer is completely dissolved at about 30 ° C. The cis isomer precipitates as a crystalline solid at a temperature of about 30 to about 40 ° C. in the same solvent.

A suitable solvent is selected from the group consisting of a mixture with one or more alcohols with water with a mixture of an alcohol, and the formula R ¹ OH with an alcohol of formula R ¹ OH having the formula R ¹ OH, where R ¹ is C ₁ -C ₅ alkyl.

Preferred solvent is methyl alcohol.

After the mixture of cis-trans isomers was dispersed in the solvent, the mixture was heated to a temperature of about 40 to about 55 ° C. and maintained for at least 4 hours. Preferably the mixture is heated to about 40 to about 45 ° C. for at least about 7 hours.

In the next step, the mixture is cooled slowly to separate the less soluble cis isomers as crystalline solids. In general, the mixture is cooled to a temperature of about 0 to about 35 ° C. for about 96 hours; Preferably the mixture is cooled to about 25 ° C. for about 72 hours.

Finally, the mixture is cooled to about 0 to about 5 ° C for about 1 hour. In this step, the solid consists of pure cis isomers.

Referring to formula (I), the carbon atoms C ₁ and C ₂ are both asymmetric carbon atoms, each having a stereogenic center in the molecule of formula (I).

Compounds of formula (I) contain two pairs of enantiomers. Between the two pairs, stereoisomers are diastereomers and are generally expected to have different physical properties such as solubility in typical solvents.

Cis and trans isomers of the present invention refer to the coordination relationship between the nitro and aryl groups on C ₂ and C ₁ .

Interconversion of cis and trans isomers of the present invention is illustrated by the presence of transition compounds wherein the C ₂ carbon is non-chiral. C ₂ non-chiral carbon atoms are formed by bond cleavage at the C ₂ carbon atom position. Preferably, the bond split occurs at the C ₂ -H bond, thereby protoning Is separated, leaving a resonance stabilized carboion ion at the C ₂ position. Requantization reaction epimerizes the transition state back to cis or trans isomers.

The splitting of both at C ₂ carbon atoms is facilitated by the presence of an electron withdrawing group attached to C ₂ . Suitable electron drag groups are selected from the group consisting of nitro, nitroso, nitrile, sacyanato, isocyanato, aryl substituted by nitrile, sulfonyl, and carbonyl. Preferably, the electron withdrawing group attached to C ₂ is a nitro group.

Cis coordination is preferred in the present invention, and the equilibrium of the solution is maintained by heating at a ratio of 3: 1 cis-trans through an interconversion step. Through crystallization and interconversion of the cis isomer, the trans isomer is completely converted into the cis isomer.

The present invention provides a novel process for the preparation of pure isomers through the interconversion of mixtures of cis and trans isomers of the compounds of formula (I) and separation of less soluble, more crystalline cis isomers.

In this method the mixture of isomers is dispersed in an inert solvent and then completely dissolved by applying heat. Equilibration takes place between dissolved isomers that are interconvertible through the non-chiral steric center. Through the selection of the appropriate solvent and the appropriate heating and cooling conditions, the isomeric mixture is completely converted to cis coordination.

Formula I

Stereochemical terms found in the present specification and claims are defined as follows:

Asymmetric atoms are atoms bonded to four different atoms or groups. The position of the asymmetric atom is called chiral center or steric center, and molecules containing one or more chiral centers are called chiral molecules. Chiral molecules are not identical in their mirror image and do not overlap.

Isomers are compounds that have the same molecular structure but differ in the nature of their bonding order or in the arrangement of their atoms in space. Stereoisomers are isomers that differ only in the arrangement of their atoms in space. Enantiomers are stereoisomers that are mirror images of one another, but do not overlap. Racemates are mixtures of enantiomers which exist together in equal amounts.

The cis and trans isomers contain atoms or groups protruding on the same direction (cis) or opposite direction (trans) of the reference plane. For diastereomers containing two asymmetric carbon atoms, the reference plane is projected through the two asymmetric atoms.

Epimerization reactions are reversible changes of one diastereomer to another diastereomer.

Conversion is an irreversible change of one stereoisomer to another stereoisomer.

The structure of the cis and trans isomers in the present invention relates to the coordination around the stereogenic center located at C ₁ and C ₂ of formula (I). Specifically, the cis and trans coordination disclosed herein relates to the spatial relationship between C ₁ -Ar bonds and C ₂ -NO ₂ bonds.

In the initial stage of the invention, the mixture of isomers is dispersed in a solvent in which the cis isomer has a lower solubility than the trans isomer.

The dispersion is heated for an extended period of time to dissolve all of the trans isomers and some of the cis isomers. Solution equilibration of the cis and trans isomers is initially made to have a ratio of about 1: 1. The cis and trans isomers are interconverted during the heating period and the solution equilibrium is converted to a ratio of cis to trans from about 4: 1 to about 3: 1. In a preferred embodiment the equilibrium ratio of cis to trans isomer in solution is 3: 1.

During the cooling step, more crystalline, less soluble cis isomers precipitate out of solution. The 3: 1 equilibrium ratio in solution is again achieved through additional interconversion of the trans to the cis isomer. The slow cooling process continues until the solids are substantially all cis isomers.

Interconversion of cis and trans isomers occurs via planar transition compounds formed by cleavage of bonds in C ₂ . In general, the formation of intermediate transition compounds is favored by stabilizing resonance structures.

In a preferred embodiment of the present invention, bond cleavage occurs between a C ₂ carbon atom and a hydrogen atom attached to the carbon atom such that the proton ( Separation) and conversion to planar non-chiral carboion ions with the resonance structure I _R of the C ₂ carbon atom.

Resonance stabilization reactions according to formula I _R favor the formation of flat carboanions. Proton at C ₂ carbon atom Removal of H atoms is facilitated by nitro groups in close proximity which make the H atoms very unstable hydrogen atoms.

Without wishing to be bound by theory, the inventors believe that interconversion of the isomers is best explained by chemical conversion at the non-chiral carbon atom C ₂ in the transition state I _R. Specifically, the re-quantization in the reaction C ₂ determines the cis or trans relationship between the aryl group and the C ₁ to C ₂ of the night. Therefore, the cis and trans isomers of formula I are in solution equilibrium as illustrated in Scheme I.

Generally, the heating step of the present invention takes place at a temperature of about 40 to about 55 ° C. and is maintained for at least 4 hours. The cooling step occurs at a temperature of about 0 to about 35 ° C. over about 96 hours. In a preferred embodiment the requantization at C ₂ is preferred for cis coordination and the solution equilibrium concentration of cis / trans is 3: 1. Preferably, the 3: 1 ratio of cis / trans is maintained for at least about 7 hours at a temperature of about 40 to about 45 ° C. and when the solvent is methyl alcohol. The mixture is preferably cooled at 40 ° C. at about 35 ° C. for about 10 hours and then preferably at 35 ° C. at about 30 ° C. for about 4 hours. Cooling is preferably continued for about 48 hours at 30 ° C to about 25 ° C. Finally, the mixture is cooled at about 0-5 ° C. for about 1 hour. Here, the solid was completely converted to cis coordination.

Compounds of formula (I) include substituted ethanes comprising carbon atoms C ₁ and carbon atoms C ₂ , wherein C ₁ is an asymmetric carbon atom attached to four different substituents in a single bond. Four substituents are -H, -Ar, -N = CH-Ar, and C ₂ . C ₂ is a second asymmetric carbon atom attached to —H, —NO ₂ , C ₁ and — (CH ₂ ) ₂ C (OMe) ₂ R as a single bond. According to established chemistry principles well known to those skilled in the art, compounds having n asymmetric atoms include the number of stereoisomers not exceeding 2 ⁿ . Compounds of formula I contain the compounds of the formula 2 ² or 4 stereoisomers Ia, Ib, Ic, and Id described below.

Compounds of formulas (la)-(d) have the same molecular formula. That is, each compound consists of the same substituents on C ₁ and C ₂ , but all four compounds differ in the arrangement of substituents on C ₁ and C ₂ .

Compounds of formulas (Ia) and (Ib) are mirror images of each other, and compounds of formulas (Ia) and (Ib) are pairs of enantiomers that cannot be superimposed on one another. Compounds of formulas Ic and Id are mirror images of each other, and compounds of formulas Ic and Id are another pair of enantiomers that cannot be superimposed on one another.

Compounds of formulas (Ia) and (Ic) are diastereoisomers because they are not mirror images of each other; Similarly, compounds of formulas Ia and Id, Ib and Ic, and Ib and Id are diastereoisomers. Diastereomers typically have different properties such as boiling point, melting point, and solubility.

As can be seen in the above structural formulas for Formulas Ia, Ib, Ic and Id, the compounds of the present invention are compounds of formula Ia in cis configuration and compounds of formula Ib in enantiomers thereof and compounds of formula Ic in trans configuration and their It is present as a compound of formula Id which is an enantiomer.

Scheme 2 discloses a procedure for the preparation of compounds of formula I in a 1: 1 cis to trans ratio as disclosed in WO 01/77100.

In Scheme 2, nitromethane is added to the alkyl vinyl ketone to form the corresponding 1-nitro 4-oxo alkanes, which in the next step are aromatic aldehydes in the presence of trimethyloformate, ammonium acetate as the amine source. Reaction with 2 equivalents of PhCHO affords compounds of formula I in a ratio of about 1: 1 cis to trans.

As disclosed in WO 01/77100, compounds of formula (I) in the form of a mixture of cis and trans isomers, including racemates, have specific cis- showing pharmacological activity in the treatment and prevention of central nervous system diseases. It is a useful intermediate in the synthesis of rich benzamide piperidine compounds. Representative benzamide piperidine compounds are those of Formula VI.

Wherein the phenyl substituent on the piperidine ring atom 2 and the amino substituent on the ring atom 3 are cis configuration; The alkyl group on ring atom 6 is trans coordinating to the phenyl group on atom 2 and Ar ¹ is selected from mono- or di-substituted aryl or heteroaryl.

Examples of certain compounds of formula VI are the following compounds and their pharmaceutically acceptable salts:

7-[(6-isobutyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

6-methoxy-3-methyl-5-[(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclo Propa [a] naphthalen-2-one;

[1- (2-Dimethylamino-ethyl) -2-phenyl-piperidin-3-yl]-(2-methoxy-5-trifluoromethoxy-benzyl) -amine;

6-methoxy-1-methyl-7-[(2-phenyl-octahydro-cyclopenta [b] pyrrol-3-ylamino) -methyl] -3,4-dihydro-1H-quinolin-2-one ;

(2-methoxy-5-trifluoromethoxy-benzyl)-(1- [1,2,4] oxadiazol-3-ylmethyl-2-phenyl-piperidin-3-yl) -amine;

7-{[1- (imidazol-1-yl-acetyl) -2-phenyl-piperazin-3-ylamino] -methyl} -6-methoxy-1-methyl-3,4-dihydro- 1H-quinolin-2-one;

6-methoxy-3-methyl-5-[(6-methyl-2-phenyl-piperidin-3-ylamino) -methyl] -1,1a, 3,7b-tetrahydro-3-aza-cyclo Propa [a] naphthalen-2-one;

6-methoxy-1-methyl-7- [6-ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -3,4-dihydro-1H-1,1a, 3,7b- Tetrahydro-3-aza-cyclopropa [a] naphthalen-2-one;

6-methoxy-1-methyl-3,3-cyclopropyl-7- [6-ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -1,3-dihydro-indole-2 -On;

5-[(6-ethyl-2-phenyl-piperidin-3-ylamino) -methyl] -6-methoxy-3-methyl-1,1a, 3,7b-tetrahydro-3-aza-cyclo Propa [a] naphthalen-2-one.

According to the abovementioned references, when the mixture of racemic diastereomers of formula (I) is an intermediate to the compound of formula (VI), the stereoselective reduction in the subsequent step is a cis-rich compound of formula (VI) To calculate.

According to Scheme 3, the compound of formula I is converted to cyclic imine III, followed by reduction of piperidine IV substituted with a hydrogen source such as lithium aluminum hydride at −78 ° C. in the presence of a Lewis acid such as trimethylaluminum. In the resulting piperidine IV, the ethyl group at position 6 of the ring is trans relative to the aryl group at position 2. The compound of formula IV is converted to oxime at position 3, followed by stereospecific reduction with hydrogen and Raney nickel to obtain cis-rich coordination for the Ar group at position 2. Cis coordination is retained through the final step of the cis-rich compound of formula VI. The route using a 1: 1 mixture of cis / trans isomers of formula (I) has the serious disadvantage that complicated steps and purification with loss of yield are required to obtain compounds of formula (VI). The inventors recognize the need to prepare the pure cis isomers of formula V and provide compounds of formula VI having preferred stereochemistry in a more direct and inexpensive manner. Pure isomers of formula (I) provide a novel process that uses fewer steps to achieve and maintain the desired cis stereochemistry.

Scheme 4 illustrates an alternative route to the cis isomer of Formula VI using the pure cis compound of Formula I prepared according to the present invention. Based on the reaction sequence disclosed in WO 01/77100, this novel process provides compounds of formula VI directly as pure cis isomers with improved yields and fewer steps.

According to Scheme 4, cis enamine IIa is obtained by cyclization of the cis isomer of formula I followed by nitrogen protection. Subsequent steps of reduction and deprotection yield a compound of formula V with preferred cisnitrophenyl stereochemistry.

In a preferred embodiment of the invention, the compound of formula (I) is benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine.

Compounds of formula VI, and the intermediates disclosed in the above schemes, can be isolated and purified by conventional procedures such as recrystallization or chromatographic separation.

The compounds of formula VI and their pharmaceutically acceptable salts can be administered to the mammal via oral, parenteral (subcutaneous, intravenous, muscular, sternum, and infusion techniques), rectal, nasal or topical routes. Depending on the species, weight and condition of the patient to be treated and the particular route of administration chosen, these compounds are generally most preferably in single or divided doses (ie, in dosages of from about 0.01 to about 1500 mg per day). In 1 to 4 doses per day). However, dosage levels ranging from about 0.5 mg to about 500 mg per kg of body weight per day are most preferably used. Nevertheless, changes may occur depending on the species of animal to be treated and the individual response to the medicament, as well as the type of pharmaceutical formulation selected and the time and interval at which such administration is performed. In some cases, dose levels below the lower limit of the range may be more appropriate, while in other cases, higher doses may be used without causing any harmful side effects, in which case higher dose levels may be used first during the day. It is divided into several smaller portions for the administration of.

The compound of formula VI may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes indicated above, and such administration may be carried out in one or multiple doses. More specifically, the novel therapeutic agents of the invention can be administered in a wide range of different dosage forms. That is, the therapeutic agent may be used in various pharmaceutically acceptable inert carriers and tablets, capsules, lozenges, troches, hard candy, powders, sprays, creams, salves, suppositories, jelly, gels, pastes, lotions. , Ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, various non-toxic organic solvents, and the like. Moreover, oral pharmaceutical compositions may be appropriately sweetened and / or flavored. Generally, the therapeutically-effective compounds of the present invention are present in such dosage forms at concentration levels ranging from about 5.0 to about 70% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine are used as disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates. It can be used in conjunction with granular binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for purification purposes. Solid compositions of a similar form can also be used as fillers in gelatin capsules; Preferred materials in this regard also include lactose or lactose as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are preferred for oral administration, the active ingredient may be a variety of sweetening or flavoring agents, colorants or dyes, and preferably emulsifying and / or suspending agents, water, ethanol, propylene glycol, glycerin And various diluents such as combinations thereof.

For parenteral administration, a solution of the compound of formula VI in sesame oil or peanut oil or in aqueous propylene glycol can be used. The aqueous solution should be properly buffered if desired (preferably above pH 8), and the solution dilution should first be isotonic. Such aqueous solutions are suitable for intravenous injection purposes. Oil solutions are suitable for intraarterial, intramuscular and subcutaneous injection purposes. The preparation of such solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

In addition, in the treatment of inflammatory conditions of the skin, it is also possible to administer the compounds of formula VI locally, which are carried out according to standard pharmaceutical practice with creams, jelly, gels, pastes, patches, ointments and the like.

The activity of the compound of formula VI as a substance P antagonist is measured by its ability to interfere with the binding of substance P at the receptor site of IM-9 cells using radioligands. Substance P antagonist activity of the compounds disclosed herein is assessed using standard assay procedures reported by DG Payan et al., The Journal of Immunology , 133, 3260 (1984). The method measures the concentration of individual compounds required to reduce the amount of radiolabeled substance P ligand to 50% at the receptor site in isolated bovine tissue or IM-9 cells to obtain characteristic IC ₅₀ values for each compound tested. It involves doing. More specifically, the inhibition of [ ³ H] SP binding to human IM-9 cells by the compound is characterized by assay buffer (50 mM Tris-HCl, pH 7.4, 1 mM MnCl ₂ , 0.02% bovine serum albumin, bacitracin (40). Μg / ml), lupeptin (4 μg / ml), chymostatin (2 μg / ml) and phosphoramidone (30 μg / ml). The reaction is started by adding cells to assay buffer containing 0.56 nM [ ³ H] SP and various concentrations of compound (total volume 0.5 ml) and incubated at 4 ° C. for 120 minutes. The culture is terminated by filtration with a GF / B filter (pre-absorbed for 2 hours in 0.1% polyethyleneamine). Nonspecific binding is defined as the remaining radioactivity in the presence of 1 uM SP. The filter is placed in a tube and counted using a liquid scintillation counter.

Compounds of formula VI are tested and one or more stereoisomers of each of these compounds show an affinity of at least 600 nM of binding, measured as K ₁ .

The activity of the compound of formula VI against general anxiety disorder can be measured by inhibition of the GR73632-induced tapping experiment in Gerbilus rats. More specifically, Gerbilus rats are lightly anesthetized with ether and the skull surface is exposed. GR73632 or vehicle (PBS, 5 μl) is administered directly to the lateral ventricle through a 25 gauss needle inserted 4.5 mm below the bregma. After dosing, Gerbilous rats were individually placed in a 1 L beaker and repeated hind limb tapping was monitored. Some compounds prepared according to Scheme 4 were tested according to this experimental method. As a result, it was found that the compound of formula VI has good antagonist activity against substance P, in particular good activity against CNS disease while reducing side effects.

The invention is illustrated by the following examples. However, it will be understood that the invention is not limited to the specific parts of this embodiment. Melting point is not accurate. Quantum nuclear magnetic resonance spectroscopy ( ¹ H NMR) and ¹³ C nuclear magnetic resonance spectroscopy were measured for solutions in deuterochloroform (CDCl ₃ ) or in CD ₃ OD or CD ₃ SOCD ₃ and the peak position was determined by tetramethylsilane ( TMS) in downfield in parts per million (ppm). The peak shape is indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.

Preparation Example 1

6-nitro-hexan-3-one

A solution of sodium methoxide in MeOH (4.6M, 6.46 mL, 29.7 mmol, 0.25 equiv) at −30 ° C. was diluted with ethyl vinyl ketone (11.78 mL, 119 mmol, 1 equiv) and nitromethane in MeOH (30 mL, 3 vol). (19.3 mL, 357 mmol, 3 equiv) was added to the solution. The reaction mixture was then warmed to −10 ° C. for 1.5 h, quenched with half saturated ammonium chloride solution (100 mL) and then extracted with dichloromethane (3 × 100 mL). The combined organics were dried over sodium sulphate, concentrated and then stripped from toluene (2 × 100 mL) and MeOH (100 mL) to about 95% purity 6-nitro-hexane-3- as measured by ¹ H NMR. 15.2 g of warm was obtained.

¹ H NMR (CDC13) δ4.32 (t, 2H, J = 6.6 Hz), 2.46 (t, 2H, J = 6.6 Hz), 2.32 (m, 2H), 2.12 (m, 2H), 0.92 (t, 3H, J = 7.5 Hz).

Preparation Example 2

7-nitro-heptan-4-one

Sodium methoxide solution in MeOH at −30 ° C. was added to the 1-hexen-3-one and nitromethane solution in MeOH. The reaction mixture was then warmed to −10 ° C. for 1.5 h, quenched with half saturated ammonium chloride solution and then extracted with dichloromethane. The combined organics were dried over sodium sulfate, concentrated and then stripped from toluene and MeOH to give 7-nitro-heptan-4-one.

Example 1

Cis-benzylidene- (5,5-dimethoxy-2-nitro-1-cetyl) -amine

Camphorsulfonic acid (CSA, 1.11 g, 4.78 mmol, 0.05 equiv) was prepared in 6-nitro-hexane-3-one of Preparation Example 1 in MeOH (28 mL, 2 vol) and trimethyl orthoformate (28 mL, 2 vol). (13.9 g, 95.7 mmol, 1 equiv) was added to the solution and the resulting solution was stirred at room temperature for 30 minutes. A solution of ammonium acetate in MeOH (120 mL) and benzaldehyde (19.5 mL, 191 mmol, 2 equiv) was added and the solution was stirred at room temperature. The decision appeared after about 6 hours. The solid measured by ¹ H NMR was a 1: 1 mixture of cis / trans benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine. The reaction was then heated at 40 ° C. for 7 hours. The solids were all cis benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine. However, the filtrate still showed a mixture of cis and trans materials. The reaction was cooled to 35 ° C., stirred overnight, then cooled to 30 ° C. for 4 hours, and finally cooled to room temperature. After stirring over the weekend, the reaction mixture was cooled to 0 ° C. The reaction was collected by filtration to yield 24.3 g (66%) of benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine with only cis nitrophenyl stereochemistry. It was. The previous steps are summarized in Table 1 below.

¹ H NMR (CDC13) δ8.2 (s, 1H), 7.72 (m, 1H), 7.35 (m, 8H), 5.03 (m, 1H), 4.65 (d, 1H, J = 10 Hz), 3.04 ( s, 3H), 2.98 (s, 3H), 1.50 (m, 4H), 1.42 (m, 2H), 0.65 (t, 3H, J = 7.5 Hz).

Example 2

Camphorsulfonic acid was added to the 7-nitro-heptan-4-one solution of Preparation Example 2 in MeOH and trimethyl orthoformate, and the resulting solution was stirred at room temperature for 30 minutes. A solution of ammonium acetate in MeOH and benzaldehyde was added and the solution was stirred for 6 hours at room temperature. The reaction was then heated at 40 ° C. for 7 hours. The reaction was cooled to 35 ° C., stirred overnight, then cooled to 30 ° C. for 4 hours, and finally cooled to room temperature. After stirring over the weekend, the reaction mixture was cooled to 0 ° C. The reaction was collected by filtration to yield benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-octyl) -amine with only cis nitrophenyl stereochemistry.

Example 3

Camphorsulfonic acid was added to the 6-nitro-hexan-3-one solution of Preparation Example 1 in MeOH (28 mL, 2 vol) and trimethyl orthoformate, and the resulting solution was stirred at room temperature for 30 minutes. A solution of ammonium acetate in MeOH and 4-chlorobenzaldehyde was added and the solution was stirred for 6 hours at room temperature. The reaction was then heated at 40 ° C. for 7 hours. The reaction was cooled to 35 ° C., stirred overnight, then cooled to 30 ° C. for 4 hours, and finally cooled to room temperature. After stirring over the weekend, the reaction mixture was cooled to 0 ° C. The reaction was collected by filtration to give only (4-chloro-benzylidene)-[1- (4-chloro-phenyl) -5,5-dimethoxy-2-nitro-heptyl with cis nitrophenyl stereochemistry ] -Amine was obtained.

Example 4

Campersulfonic acid was added to the 6-nitro-hexan-3-one solution of Preparation Example 1 in MeOH and trimethyl orthoformate, and the resulting solution was stirred at room temperature for 30 minutes. A solution of ammonium acetate in MeOH and benzaldehyde was added and the solution was stirred overnight at room temperature. The reaction was then heated at reflux for 3-4 hours. The reaction was cooled to 50 ° C. for 8 hours, then to 30 ° C. for 8 hours, and finally to room temperature for 8 hours. After stirring over the weekend, the reaction mixture was cooled to 0 ° C. for 1 h. The product was collected by filtration to yield benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine with only cis nitrophenyl stereochemistry.

Example 5

Campersulphonic acid was added to the 6-nitro-hexan-3-one solution of Preparation Example 1 in isopropanol and trimethyl orthoformate and the resulting solution was stirred at room temperature for 30 minutes. Asopropanol and ammonium acetate solution in benzaldehyde were added and the solution was stirred at room temperature for 6 hours. The reaction was then heated at 40 ° C. for 7 hours. The reaction was cooled to 35 ° C., stirred overnight, then cooled to 30 ° C. for 4 hours, and finally cooled to room temperature. After stirring over the weekend, the reaction mixture was cooled to 0 ° C. The product was collected by filtration to yield benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine with only cis nitrophenyl stereochemistry.

Claims (14)

A process for preparing pure cis isomers from a mixture of cis-trans isomers of formula (I), a. Dispersing a mixture of cis and trans isomers of formula (I) in an inert solvent in which the cis isomer is substantially less dissolved than the trans isomer; b. Heating the dispersion such that the trans isomer is completely dissolved and the cis isomer is dissolved at least 10% by weight; c. Maintaining a heating step to allow interconversion of the cis and trans isomers; d. Cooling the mixture to crystallize into cis isomers; And e. A process for preparing the pure cis isomer from the cis-trans isomer of formula (I) comprising the step of separating the crystalline cis isomer from the solvent: Formula I Where Ar is phenyl or naphthyl optionally mono- or di-substituted by C _1-5 alkyl, C _1-5 alkoxy, halogen, trifluoromethyl, ester or amido; R is C _1-5 alkyl. The method of claim 1, The compound of formula (I) consists of a chiral carbon atom C ₁ and an adjacent chiral carbon atom C ₂ ; C ₂ is attached to a hydrogen atom and a strong electron withdrawing group selected from the group consisting of nitro, nitroso, nitrile, cyanato, isocyanato, nit substituted aryl, sulfonyl and carbonyl; At least one atom or group attached to C ₁ is different from the atom or group attached to C ₂ . The method of claim 1, Wherein the interconversion of the cis and trans isomers comprises bond cleavage and reformation at C ₂ carbon atoms. The method of claim 3, wherein Wherein the bond splitting and reforming occurs at a bond between a C ₂ carbon atom and a hydrogen atom attached thereto. The method of claim 4, wherein A method of preparation wherein the bond cleavage produces a non-chiral transition compound having the following resonance structure: The method of claim 5, A process for producing cis and trans isomers in a solvent which are interconverted through the transition compound. The method of claim 1, Wherein the crystallization of the cis isomer results in further interconversion of the dissolved trans isomer to the cis isomer. The method of claim 1, Wherein the dispersed cis and trans isomer mixture consists of solid cis and trans isomers in a weight ratio of about 1: 1. The method of claim 4, wherein Wherein at least some of the cis and trans isomers are present in solution equilibrium of the cis and trans isomers in a ratio of 3: 1. The method of claim 1, Wherein the heating step continues for about 4 to about 10 hours. The method of claim 1, _Wherein R is C _1-5 alkyl. The method of claim 1, A process wherein Ar is phenyl. The method of claim 1, A process of formula I wherein the compound of formula I is benzylidene- (5,5-dimethoxy-2-nitro-1-phenyl-heptyl) -amine. The method of claim 1, Inert solvent is selected from the group consisting of a mixture with one or more alcohols with water with a mixture of an alcohol, and the formula R ¹ OH with an alcohol of formula R ¹ OH having the formula R ¹ OH, where R ¹ is C ₁ -C ₅ alkyl.